An occasion of drug taking may be a passing indulgence of an adolescent, perhaps initiated in a moment of immature judgment. All too often, the drug taking can become repetitive and may lead to a syndrome of abuse or addiction, possibly in an interaction of inherited vulnerability traits with environmental conditions and processes. The development of addiction and the dependence syndrome in adolescents are emotion-laden, controversial, and often misunderstood topics. Public opinion leaders often do not appreciate the scientific evidence that tends to favor a disease concept of addiction or dependence on alcohol, tobacco, and other drugs such as cocaine or cannabis (McLellan, Lewis, O'Brien, & Kleber, 2000). This evidence includes a neuronal basis for many of the prominent clinical features of dependence (Dackis & O'Brien, 2003), genetic vulnerability (Vanyukov & Tarter, 2000), and a characteristic chronic, relapsing course that resembles that of many medical illnesses. Unfortunately, these biological bases of addiction are often forgotten or misunderstood by a nonetheless opinionated American public that can view adolescent drug problems as purely behavioral and morally objectionable. Consequently, many affected adolescents end up being managed by their parents, school authorities, or the judicial system rather than being treated in specialized adolescent treatment programs. Even those seeking treatment often discover that appropriate programs do not exist in their geographic region or are difficult to access because of low capacity or managed care policies. While there would be a public uproar if treatment were not available to adolescents with head injuries, diabetes, or cancer, obvious disparities in addiction treatment have been tolerated for decades and may well reflect public skepticism about the biological bases of drug dependence and addiction. Unfortunately, we have much to learn about the onset, nature, and treatment of these conditions in adolescents. It is our contention that gaps in our knowledge should be addressed with research and clinical experience, and not cited to justify an inadequate treatment infrastructure.

Syndromes of alcohol, tobacco, and other drug abuse and addiction have been defined and redefined over the past several decades and these definitions have now achieved international acceptance. The central clinical features generally include (a) disturbances of mental life in the form of obsession-like ruminations or even craving for drugs or drug-related experiences, (b) disturbances of behavior in the form of compulsion-like repetitive drug-taking or drug-related behaviors to the detriment of normal activities, and (c) manifestations of neuroadaptation to drug exposure, in the form of pharmacological tolerance and (sometimes) observable and characteristic withdrawal syndromes when there is an abrupt cessation of drug use. Many definitions of abuse and addiction reference a loss of control during cycles of euphoria and craving. Any definition must account for the continuum of severity that ranges from minimal use with limited consequences on one end to compulsive use with serious functional impairment on the other end. Some adolescents show progressive impairment and move along the continuum whereas others remain at a relatively stable level of severity. The American Psychiatric Association's (1994) Diagnosis and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) uses the label substance abuse to describe use with limited negative consequences, whereas the term dependence refers to a generally more serious loss of control of drug taking and a clinical syndrome with a running together of the clinical features mentioned above. The term dependence as used in the official DSM-IV manual often leads to semantic confusion with dependence in the pharmacological sense, which is a normal response to repeated use of many different types of medications, including drugs for the treatment of hypertension, depression, and pain. Thus many clinicians prefer the term addiction when referring to dependence as defined in DSM-IV. This definition applies the same diagnostic criteria to all pharmacological classes, acknowledging that similar disturbances of mental life and behavior, as well as manifestations of neuroadaptation, may develop regardless of whether the drug taking involves alcoholic beverages, tobacco (nicotine), or other drugs such as cocaine, heroin, or cannabis. Accordingly, alcohol is grouped with other dependence-producing drugs in the DSM-IV classification and will be categorized as such in this volume.

Seeking a fundamental understanding of the processes that lead toward drug addiction, clinical investigators have found evidence that drug-induced euphoria is linked to pharmacological activation of reward-related brain regions that normally mediate natural reward, including reward circuits influenced by food, sex, and drinking fluids (Dackis & O'Brien, 2003b). Reward-related circuits that have evolved over millions of years to ensure survival may actually be dysregulated by the chronic use of drugs. The clinical features of craving, loss of control, and impaired hedonic function also have linkages with the dysregulation of brain reward centers (Dackis & O'Brien, 2001, 2003b).

Tolerance is manifested in an escalation of drug dose to achieve a stated level of drug-induced effect. The process of developing tolerance can begin with the first exposure to the drug, with subsequent compensatory neuradaptational changes that often oppose the acute effect of the drugs. For example, the chronic administration of heroin and diazepam can produce so much tolerance that a 100-fold increase in dose is required to produce certain pharmacological effects that were apparent at the first low dose. Tolerance may also occur over brief periods, as evidenced by ever-decreasing euphoria with successive cocaine doses during a protracted binge. Tolerance develops more rapidly to some drug effects than to others, and drug-induced euphoria typically requires ever-increasing doses; in contrast, toxic effects may not initially require a greater dose (e.g., heroin-induced respiratory depression). Individual variability in rates of development of tolerance appear to be genetically determined and may help explain variations in the risk of drug overdose.

In contrast with pharmacological tolerance as ordinarily defined, a reverse tolerance or sensitization can occur, as manifest in an increased drug response after repeated administration. For instance, successive equal doses of cocaine can be followed by motor activity increases (i.e., the opposite of what is expected if tolerance has developed) in rats given the drug at daily intervals. Examples of reverse tolerance or sensitization in humans are difficult to demonstrate but may include cocaine-induced psychosis, seizures, and cue-induced craving (Dackis & O'Brien, 2001). Tolerance and sensitization phenomena are influenced by genetic factors that affect receptor responses and the distribution of drugs in the body (pharmacokinetics) and the nervous system adaptations (pharmacodynamics) once drug exposure has occurred.

A withdrawal syndrome is seen most clearly when there is abrupt discontinuation of repetitive drug-taking. It is possible to conceive of the withdrawal features as manifestations of compensatory or homeostatic brain changes that have been established in response to chronic or repeated drug exposures. If the drug is abruptly discontinued, these changes are suddenly unopposed and there can be a rebound in the form of a characteristic cluster of withdrawal signs and symptoms. These clusters or drug withdrawal syndromes can vary markedly across classes of addictive drugs and typically include clinical features that are opposite those seen during intoxication. The onset, duration, and clinical course of withdrawal also can vary from one individual to another. It should be emphasized that withdrawal from alcohol or sedative or hypnotic agents (especially barbiturates) is potentially lethal and often requires intensive medical inpatient treatment. Treatment of drug withdrawal (detoxification) is often accomplished by administering descending doses of a medication with the same types of action as the dependence-producing drug. Therefore, opioids (such as methadone) are used to reverse heroin withdrawal, longer-acting benzodiazepines are used to counter withdrawal from shorter-acting benzodiazepine drugs, and longer-acting barbiturates are used to counter withdrawal due to shorter-acting barbiturates. In addition, benzo-diazepines and barbiturates effectively reverse the alcohol withdrawal syndrome, based on their shared action on underlying neuronal (GABA) circuitry. Although detoxification is an important clinical intervention that allows the brain to equilibrate in the absence of the dependence-producing drug, detoxification is seldom sufficient to arrest the cycle of craving and euphoria. Consequently, detoxified patients require referral to continued drug rehabilitative treatment.

As we seek an understanding of vulnerability to drug dependence and addiction, we can turn

to three major domains of influence. This triad includes (1) the drug used (the “agent”), (2) the constitutional characteristics of the user (the “host”), and (3) the physical and psychosocial setting (the “environment”). As we look across classes of drugs, the nature and potency of drug-induced euphoria vary considerably, and this euphoria may be an important reinforcer of repetitive drug-taking behavior. Among addiction specialists, there is a general consensus about a hierarchy of addictiveness or dependence liability among drugs, although it is arguable how central stimulants, opioids, alcohol, nicotine, sedative and hypnotics, marijuana, and hallucinogens should be specifically ranked. Animal models provide one means of gauging the reinforcing functions of each drug as an agent in the process of developing drug dependence. When properly equipped with intravenous delivery systems, laboratory animals will self-administer various drugs with varying enthusiasm. For instance, laboratory animals with unlimited access to cocaine or amphetamine generally will self-administer these agents until they die; in contrast, training animals to self-administer alcohol or cannabis can be difficult. Evidence for the biological basis of drug reward includes the phenomenon that animals will self-administer drugs like cocaine without special training, as well as the finding that nearly all drugs with dependence liability (cocaine, amphetamine, heroin, alcohol, nicotine, marijuana) share a common action of activating brain reward systems, as indicated by elevated dopamine levels in the nucleus accumbens (Dackis & O'Brien, 2003b). In fact, researchers routinely use this neurochemical signature of drug reward to screen the addictive potential of compounds synthesized in pharmaceutical research and development process. Natural rewards such as food, water, and sex also increase dopamine levels in the nucleus accumbens, consistent with the notion that these drugs produce euphoria by activating natural pleasure pathways. Although dopamine plays a central role in natural and drug-induced reward, there is also evidence that endogenous opioids, glutamate, γ-aminobutyric acid (GABA), and serotonin systems are mechanistically involved.

The ability of a drug to induce euphoria in humans is correlated with its dependence liability or addictiveness and can be greatly enhanced when the drug is taken by routes of administration that produce rapidly rising brain levels of the agent. The importance of the route-of-administration principle is illustrated in the history of cocaine use. People living in the Andes Mountains have chewed coca leaves since antiquity with few deleterious effects, largely because cocaine brain levels increase very slowly when the drug is absorbed through the buccal mucosa. However, once pure cocaine was chemically isolated from the coca leaf in the form of hydrochloride powder (HCl), it became possible to administer high doses by the more efficient intranasal and intravenous routes. Once cocaine HCl powder was administered intravenously or intranasally, its toxic effects became more obvious. During the 1980s the by-then illegal cocaine marketplace changed markedly when an underground pharmaceutical innovation appeared in the form of crack-cocaine, which is heated and vaporized so that the fumes can be inhaled (“smoked”). Whereas a typically intranasal route of administration might yield a cocaine “high” over the course of minutes after insufflation, the onset of the cocaine high is more rapid with smoked crack-cocaine. Indeed, within seconds after being smoked and then absorbed in the lungs, the vaporized cocaine reaches the brain and an almost instantaneous rush of euphoria may fuel a crack-associated rapid emergence of the cocaine dependence process, as indicated by recent epidemiological evidence (Chen & Anthony, 2004). A similar rapid onset of effects can be achieved by injecting cocaine, but smoking crack is more convenient and more socially acceptable than injecting cocaine, especially when adolescents already have a history of smoking cigarettes or marijuana.

In addition to characteristics of the drug agent and its route of administration, host factors can contribute significantly to the onset and course of the dependence process. Disenfranchised adolescents might use drugs to gain peer acceptance, and thrill-seeking adolescents may be attracted to drug euphoria. Adolescents with clinical features of depression, anxiety, or

phobias may sometimes use drugs for relief of these symptoms. Unfortunately, chronic brain changes produced by drugs often exacerbate the very symptoms they initially alleviated, and these drugs may well produce far more psychiatric symptoms than they relieve.

Inherited traits correlated with a family history of drug dependence are also now appreciated as important host characteristics associated with the risk of becoming drug-dependent. Children of alcoholics are at increased risk of developing alcoholism, even after they have been adopted at birth and raised by nonalcoholic parents, and identical twins are more likely than fraternal twins to be concordant for alcoholism (Schuckit, 2000) and nicotine dependence (Sullivan & Kendler, 1999). Drug effects vary markedly from one individual to another and are influenced by genetic variations that affect drug absorption, metabolism, excretion, and receptor-mediated neuronal responses. Researchers are actively investigating profiles of candidate genes that encode the enzymes or other protein products related to these functions, as described in later sections about specific agents.

Individuals with extensive family history loadings for drug dependence do not necessarily become addicted, however, partly because environmental factors (supply, psychosocial norms, and peer pressure) also influence the onset and development of dependence processes. Drug supply is an essential and permissive factor that has been targeted by law enforcement initiatives. Without drug access, there can be no addiction. Aside from the physical availability of a drug, access can also be affected by its cost, with, for example, the increased use of cocaine and heroin in the past decade coinciding with the declining street price of these drugs. Psychosocial norms also affect the timing of first and subsequent uses of addictive drugs. In some communities, drug users and drug dealers are actually viewed as successful role models to be respected and emulated by young people. This unfortunate situation is often compounded by inadequate educational, vocational, and diversionary options that would otherwise offset the attractiveness of a drug-related lifestyle. Drug users often attempt to re gain control of their drug use, but relapse to compulsive use is almost inevitable. When the user returns to a neighborhood where he or she previously used drugs, the environmental cues may reflexively precipitate craving and resumption of drug taking. The role of environmental cues (people, places, and things) that can trigger craving are important research-based principles that influence both continued drug use and relapse after treatment (O'Brien, Childress, McLellan, & Ehrman, 1992). Since agent, host, and environmental factors are cumulatively involved in addictive illness, effective prevention and treatment interventions typically address all three realms.